EP1189582A2 - Materiaux composites constitues de composes de calcium et de composantes proteiques - Google Patents

Materiaux composites constitues de composes de calcium et de composantes proteiques

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Publication number
EP1189582A2
EP1189582A2 EP00951293A EP00951293A EP1189582A2 EP 1189582 A2 EP1189582 A2 EP 1189582A2 EP 00951293 A EP00951293 A EP 00951293A EP 00951293 A EP00951293 A EP 00951293A EP 1189582 A2 EP1189582 A2 EP 1189582A2
Authority
EP
European Patent Office
Prior art keywords
composite materials
protein
materials according
water
calcium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP00951293A
Other languages
German (de)
English (en)
Other versions
EP1189582B1 (fr
Inventor
Christian Kropf
Hans Dolhaine
Marcel Roth
Ulrike Brüninghaus
Albrecht Weiss
Ulrich SCHÖRKEN
Lothar Kintrup
Amerigo Pastura
Peter Wülknitz
Rüdiger KNIEP
Burkhard Eschen
Michael Meinders
Hans Laska
Stefan Müllner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
Henkel AG and Co KGaA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Henkel AG and Co KGaA filed Critical Henkel AG and Co KGaA
Priority to DE20023797U priority Critical patent/DE20023797U1/de
Priority to EP06004167A priority patent/EP1676555A3/fr
Publication of EP1189582A2 publication Critical patent/EP1189582A2/fr
Application granted granted Critical
Publication of EP1189582B1 publication Critical patent/EP1189582B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0241—Containing particulates characterized by their shape and/or structure
    • A61K8/0245—Specific shapes or structures not provided for by any of the groups of A61K8/0241
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0241—Containing particulates characterized by their shape and/or structure
    • A61K8/0283—Matrix particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/24—Phosphorous; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
    • A61L24/0084—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing fillers of phosphorus-containing inorganic compounds, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A61L27/306—Other specific inorganic materials not covered by A61L27/303 - A61L27/32
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K3/00—Use of inorganic substances as compounding ingredients
    • C08K3/01—Use of inorganic substances as compounding ingredients characterized by their specific function
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K3/00—Use of inorganic substances as compounding ingredients
    • C08K3/01—Use of inorganic substances as compounding ingredients characterized by their specific function
    • C08K3/013—Fillers, pigments or reinforcing additives
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L89/00—Compositions of proteins; Compositions of derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L89/00—Compositions of proteins; Compositions of derivatives thereof
    • C08L89/005—Casein
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L89/00—Compositions of proteins; Compositions of derivatives thereof
    • C08L89/04—Products derived from waste materials, e.g. horn, hoof or hair
    • C08L89/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/413—Nanosized, i.e. having sizes below 100 nm
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/60—Particulates further characterized by their structure or composition
    • A61K2800/65—Characterized by the composition of the particulate/core
    • A61K2800/651—The particulate/core comprising inorganic material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/60—Particulates further characterized by their structure or composition
    • A61K2800/65—Characterized by the composition of the particulate/core
    • A61K2800/654—The particulate/core comprising macromolecular material
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K2201/00—Specific properties of additives
    • C08K2201/011—Nanostructured additives

Definitions

  • the invention relates to composite materials made of nanoparticulate, sparingly water-soluble calcium salts and protein components, which due to their composition and fine structure are particularly suitable for promoting the restoration of bones and tooth enamel.
  • Phosphate salts of calcium have long been added to the formulations of dentifrices and dentifrices both as abrasive components and to promote the remineralization of tooth enamel. This applies in particular to hydroxyapatite and fluorapatite as well as to amorphous calcium phosphates and brushite (dicalcium phosphate dihydrate). Calcium fluoride has also been described several times as a component of tooth cleaning agents and as a component for strengthening the tooth enamel and for preventing caries.
  • the tooth enamel and the supporting tissue of the bones mainly consist of the mineral hydroxyapatite.
  • hydroxyapatite attaches in an orderly manner to the protein matrix in the bone or tooth, which mainly consists of collagen.
  • the formation of the hard and resilient mineral structures is controlled by the so-called matrix proteins, which in addition to collagen are formed by other proteins that attach to the collagen and thus cause a structured mineralization process, which is also referred to as biomineralization.
  • matrix proteins which in addition to collagen are formed by other proteins that attach to the collagen and thus cause a structured mineralization process, which is also referred to as biomineralization.
  • So-called bone substitutes which promote the natural biomineralization process, play an important role in the restoration of bone material.
  • Such means are also required for coating implants in order to achieve cohesive connections between the bone and the implant, with which tensile forces can also be transmitted.
  • Liquid injectable bone substitute materials are required for certain applications. A particularly small particle size is required here, but this cannot be achieved satisfactorily with the conventional bone substitutes.
  • composites of hydroxyapatite and collagen are of particular interest because they mimic the composition of the natural bone.
  • a similar situation applies to the restoration of dental material, which consists of approximately 95% hydroxyapatite.
  • Composite materials of the type described are accessible synthetically, such as. B. by B. Flautre et al. in J. Mater. Be .: Mater. In Medicine 7 (1996), 63 described.
  • the grain size of the calcium salts in these composites is above 1000 nm, which is too large to achieve a satisfactory biological effect as a remineralizing agent.
  • RZ Wang et al., J. Mater. Be. Lett. 14 (1995), 490 a production process for a composite material made of hydroxyapatite and collagen, in which hydroxyapatite with a particle size in the range from 2 to 10 nm is deposited on the collagen matrix in a uniformly distributed form.
  • the composite material is said to have a better biological activity than other hydroxyapatite-collagen composites known from the prior art because of the finely divided nature of the hydroxyapatite. As described below, however, that of RZ Wang et al. Composite material described does not sufficiently meet the need for composite materials which mimic the composition and the microstructure of natural bone and tooth material and which are suitable in a completely satisfactory manner for the remineralization of these natural materials.
  • Protein-containing composite materials known from the prior art contain proteins of animal origin, in particular those obtained from bovine material. In cosmetics in particular, however, there has been an increasing desire for products that are completely free of ingredients of animal origin. There is therefore a need for such composite materials that do not contain protein components of animal origin.
  • the protein-containing composite materials known from the prior art have, for example, due to their insoluble content and / or high molecular weight protein components, have an unfavorable dispersibility and are difficult to incorporate into the formulations required for their commercial use or have unsatisfactory dispersion stability in the preparations used.
  • the invention relates to composite materials comprising a) calcium salts which are sparingly soluble in water, selected from phosphates, fluorides and fluorophosphates, which may optionally additionally contain hydroxyl and / or carbonate groups, the calcium salts in the form of nanoparticulate primary particles having an average particle diameter in the range from 10 to 300 nm are present, and b) protein components selected from proteins, protein hydrolyzates and protein hydrolyzate derivatives.
  • Composite materials are understood to mean composites which comprise the components mentioned under a) and b) and which are microscopically heterogeneous, macroscopically but homogeneous aggregates and in which the primary particles of the calcium salts are associated with the structure of the protein component.
  • the proportion of protein components in the composite materials between 0.1 and 60% by weight, but preferably between 0.5 and 10% by weight, based on the total weight of the composite materials.
  • Primary particles are understood to mean the crystallites, ie the individual crystals of the calcium salts mentioned.
  • the diameter should be the particle diameter here the particles can be understood in the direction of their greatest length extension.
  • the mean particle diameter is to be understood as a value averaged over the total amount of the composite.
  • the determination of the particle diameter can be determined by methods familiar to the person skilled in the art, for example by the method of transmission electron microscopy (TEM).
  • TEM transmission electron microscopy
  • the average particle diameter of the nanoparticulate primary particles is preferably in the range from 10 to 150 nm, and particularly preferably they are in the form of rod-shaped particles with a thickness in the range from 2 to 50 nm and a length in the range from 10 to 150 nm to understand the smallest diameter of the rods, by length their largest diameter.
  • the spatial structure of the composite materials according to the invention consisting of a protein component and the sparingly soluble nanoparticulate calcium salts, can be seen from the example of the TEM image of a composite material made of hydroxylapatite and gelatin type A, shown in FIG. 1 (200,000 times magnification; 1 cm in the figure corresponds to 40 nm).
  • the high molecular weight protein component which takes on a three-dimensional structure essentially determined by its amino acid sequence, is supported by the rod-shaped nanoparticles made of hydroxyapatite, so the nanoparticles to a certain extent depict the spatial structure of the protein component.
  • Figure 2 shows a TEM image of the type A gelatin framework of the same composite material after the hydroxylapatite has been removed by means of a solution of ethylenediaminetetraacetate (magnification 56,000 times; 1.1 cm in the figure corresponds to 200 nm).
  • the manner in which the inorganic particles attach to the basic structure of the protein component is determined by the primary structure (amino acid sequence) and, depending on the nature of the protein component, by its secondary, tertiary and quaternary structure.
  • the spatial distribution and the quantitative extent of the attachment of the inorganic nanoparticles on the protein component can be influenced by the type and amount of the amino acids present in the protein component and thus by the selection of the protein components. For example, by selecting protein components that are rich in amino acids, aspartic acid, glutamic acid or cysteine, a particularly high loading with the poorly soluble calcium salt can be achieved. Depending on the spatial distribution of these amino acids in the protein structure, a spatially structured loading of the protein component with the poorly soluble calcium salt can also be achieved.
  • the composite materials according to the invention are thus structured composite materials in contrast to the one described by R. Z. Wang et al. Composite of hydroxyapatite and collagen described, in which evenly distributed hydroxyapatite nanoparticles are present.
  • Another major difference between the subject matter of the present invention and the prior art is the size and morphology of the inorganic component.
  • the in the by R. Z. Wang et al. Hydroxyapatite particles described have a size of 2-10 nm. Hydroxyapatite particles in this size range belong to the range of amorphous or partially X-ray amorphous substances.
  • the present invention succeeded in producing composite materials with crystalline inorganic nanoparticles in which the nanoparticles have a crystalline morphology which is clearly visible under the microscope.
  • Figure 1 shows the rod-shaped structure of the inorganic nanoparticles.
  • the structured composite materials according to the invention in contrast to the prior art, lead to a particularly effective biomineralization process. This is believed to be related to the microstructure of the composite material and in particular the size and morphology of the calcium salt crystals. It is assumed that the longitudinal axis of the calcium salt Nanoparticles are a preferred direction for further crystal growth during biomineralization.
  • Salts which are sparingly soluble in water are understood to be those which are less than 1 g / l soluble at 20 ° C.
  • Calcium salts which are preferably suitable are calcium hydroxyphosphate (Ca 5 [OH (PO- ⁇ ) 3]) or hydroxyapatite,
  • Calcium fluorophosphate (Ca 5 [F (PO 4 ) 3 ]) or fluorapatite, fluorine-doped hydroxyapatite of the general composition Ca 5 (PO) 3 (OH, F) and calcium fluoride (Ca F 2 ) or fluorite (fluorspar).
  • One or more salts in the mixture selected from the group of phosphates, fluorides and fluorophosphates, which may optionally additionally contain hydroxyl and / or carbonate groups, may be present in the mixture as the calcium salt in the composite materials according to the invention.
  • proteins are basically all proteins regardless of their origin or their production.
  • proteins of animal origin are keratin, elastin, collagen, fibroin, albumin, casein, whey protein, placental protein.
  • preferred among these are collagen, keratin, casein, whey protein, proteins of plant origin such as, for example, wheat and wheat germ protein, rice protein, soy protein, oat protein, pea protein, potato protein, almond protein and yeast protein can also be preferred according to the invention.
  • protein hydrolyzates are to be understood as degradation products of proteins such as collagen, elastin, casein, keratin, almond, potato, wheat, rice and soy protein, which are produced by acid, alkaline and / or enzymatic hydrolysis of the proteins themselves or their degradation products such as gelatin can be obtained.
  • All hydrolytically active enzymes are suitable for the enzymatic degradation, such as, for. B. alkaline proteases. Further suitable enzymes and enzymatic hydrolysis processes are described, for example, in K. Drauz and H. Waldmann, Enzyme Catalysis in Organic Synthesis, VCH-Verlag, Weinheim 1975.
  • the less degraded protein hydrolyzates include, for example, the gelatin preferred in the context of the present invention, which can have molar masses in the range from 15,000 to 250,000 D.
  • Gelatin is a polypeptide that is obtained primarily by hydrolysis of collagen under acidic (gelatin type A) or alkaline (gelatin type B) conditions.
  • the gel strength of the gelatin is proportional to its molecular weight, ie a more hydrolyzed gelatin gives a lower viscous solution.
  • the gel strength of the gelatin is given in Bloom numbers. When the gelatin is cleaved enzymatically, the polymer size is greatly reduced, which leads to very low Bloom numbers.
  • protein hydrolyzates which are customary in cosmetics and have an average molecular weight in the range from 600 to 4000, particularly preferably from 2000 to 3500, are preferred as protein hydrolyzates.
  • Protein hydrolyzates from collagen, keratin, casein and vegetable proteins are preferably used according to the invention, for example those based on wheat gluten or rice protein, the production of which is described in the two German patents DE 19502167 C1 and DE 19502168 C1 (Henkel).
  • protein hydrolyzate derivatives are to be understood as meaning chemically and / or chemoenzymatically modified protein hydrolyzates such as, for example, those with the INCI names Sodium Coeoyl Hydrolyzed Wheat Protein, Laurdimonium Hydroxypropyl Hydrolyzed Wheat Protein, Potassium Coeoyl Hydrolyzed Collagen, Potassium Undecylenoyl Hydrolyzedium Collagen and Laur Hydroxypropyl hydrolyzed collagen known compounds.
  • derivatives of protein hydrolyzates of collagen, keratin and caseins and vegetable protein hydrolyzates are preferably used, such as, for. B. Sodium Coeoyl Hydrolyzed Wheat Protein or Laurdimonium Hydroxypropyl Hydrolyzed Wheat Protein.
  • the protein component can be formed in each of the composite materials according to the invention by one or more substances selected from the group of proteins, protein hydrolyzates and protein hydrolyzate derivatives.
  • Preferred protein components are all structure-forming proteins, protein hydrolyzates and protein hydrolyzate derivatives, which are to be understood as meaning those protein components which, owing to their chemical constitution, form certain three-dimensional spatial structures which are familiar to the person skilled in the art from protein chemistry under the terms secondary, tertiary or also quaternary structure are.
  • the nanoparticulate calcium salt primary particles present in the composite materials can be enveloped by one or more surface modification agents. This can, for example, facilitate the production of composite materials in cases in which the nanoparticulate calcium salts are difficult to disperse.
  • the surface modification agent is adsorbed onto the surface of the nanoparticles and changes them in such a way that the dispersibility of the calcium salt increases and the agglomeration of the nanoparticles is prevented.
  • the structure of the composite materials and the loading of the protein component with the nanoparticulate calcium salt can be influenced by a surface modification. In this way, when using the composite materials in remineralization processes, it is possible to influence the course and speed of the remineralization process.
  • Surface modification agents are understood to mean substances which physically adhere to the surface of the finely divided particles, but which do not react chemically with them.
  • the individual molecules of the surface modification agents adsorbed on the surface are essentially free of intermolecular bonds with one another.
  • Surface modifiers are to be understood in particular as dispersants. Dispersants are also known to the person skilled in the art, for example, under the terms emulsifiers, protective colloids, wetting agents, detergents, etc.
  • Suitable surface modifiers are emulsifiers of the nonionic surfactant type from at least one of the following groups:
  • polyglycerol esters such as.
  • Partial esters based on linear, branched, unsaturated or saturated C 6/22 fatty acids, ricinoleic acid as well as 12-hydroxystearic acid and glycerin, polyglycerin, pentaerythritol, dipentaerythritol, sugar alcohols (e.g. sorbitol), alkyl glucosides (e.g. Methyl glucoside, butyl glucoside, lauryl glucoside) and polyglucosides (e.g. cellulose);
  • the adducts of ethylene oxide and / or of propylene oxide with fatty alcohols, fatty acids, alkylphenols, glycerol mono- and diesters as well as sorbitan mono- and diesters with fatty acids or with castor oil are known, commercially available products.
  • the average degree of alkoxylation corresponds to the ratio of the amounts of ethylene oxide and / or propylene oxide and substrate with which the addition reaction is carried out.
  • C 8 / i 8 alkyl mono- and oligoglycosides their preparation and their use are known from the prior art. They are produced in particular by reacting glucose or oligosaccharides with primary alcohols with 8 to 18 carbon atoms.
  • glycoside residue both monoglycosides in which a cyclic sugar residue is glycosidically bonded to the fatty alcohol and oligomeric glycosides with a degree of oligomerization of up to about 8 are suitable.
  • the degree of oligomerization is a statistical mean value which is based on a homolog distribution customary for such technical products.
  • anionic emulsifiers are droxymischethersulfate soaps, alkylbenzenesulfonates, alkanesulfonates, olefin sulfonates, alkyl ether sulfonates, glycerol ether, ⁇ - methyl ester sulfonates, sulfofatty acids, alkyl sulfates, alkyl ether sulfates, such as fatty alcohol ether sulfates, Glycerol ether, hybrid, monoglyceride (ether) sulfates, fatty acid amide (ether) sulfates, mono and dialkyl sulfosuccinates, mono- and dialkyl sulfosuccinamates, sulfotriglycerides, amide soaps, ether carboxylic acids and their salts, fatty acid isethionates, fatty acid sarcosinates, fatty acid
  • Zwitterionic surfactants can also be used as emulsifiers.
  • Zwitterionic surfactants are surface-active compounds that contain at least one quaternary ammonium group and at least one carboxylate and one sulfonate group in the molecule.
  • Particularly suitable zwitterionic surfactants are the so-called betaines such as the N-alkyl-N, N-dimethylammonium glycinate, for example the coconut alkyldimethylammonium glycinate, N-acylamino-propyl-N, N-dimethylammonium glycinate, for example the coconut acylaminopropyldimethylammonium glycinate, and 2 -Alkyl-3-carboxyl-methyl-3-hydroxyethylimidazolines each having 8 to 18 carbon atoms in the alkyl or acyl group and the cocoacylaminoethylhydroxyethylcarboxymethylglycinate.
  • betaines such as the N-alkyl-N, N-dimethylammonium glycinate, for example the coconut alkyldimethylammonium glycinate, N-acylamino-propyl-N, N-dimethylammoni
  • Suitable emulsifiers are ampholytic surfactants.
  • Ampholytic surfactants are surface-active compounds which, in addition to a C 8/18 alkyl or acyl group, contain at least one free amino group and at least one -COOH or -SO 3 H group in the molecule and are capable of forming internal salts.
  • ampholytic surfactants are N-alkylglycines, N-alkylpropionic acids, N-alkylaminobutyric acids, N-alkyliminodipropionic acids, N-hydroxyethyl-N-alkylamidopropylglycines, N-alkyltaurines, N-alkylsarcosines, 2-alkylaminopropionic acids and alkylaminoacetic acids, each with about 8 to 18 carbon atoms in the alkyl group.
  • Particularly preferred ampholytic surfactants are N-cocoalkylaminopropionate, cocoacylaminoethylaminopropionate and Ci 2 / i 8 -acylsarcosine.
  • quaternary emulsifiers are also suitable, those of the esterquat type, preferably methyl-quaternized difatty acid triethanolamine ester salts, being particularly preferred.
  • Protective colloids suitable as surface modifiers are e.g. B. natural water-soluble polymers such. B. gum arabic, starch, water-soluble derivatives of water-insoluble polymeric natural substances such.
  • B. cellulose ethers such as methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose or modified carboxymethyl cellulose, hydroxyethyl starch or hydroxypropyl guar, and synthetic water-soluble polymers, such as.
  • the surface modification agents are used in a concentration of 0.1 to 50, but preferably 1 to 20,% by weight, based on the calcium salts.
  • the nonionic surfactants in a quantity of 1 to 20% by weight, based on the weight of the calcium salt, are particularly suitable as surface modification agents.
  • the nonionic surfactants of the alkyl-C8-C16- (oligo) -glucoside type and the ethoxylates of the hardened castor oil have proven to be particularly effective.
  • the composite materials according to the invention are produced by precipitation reactions from aqueous solutions of water-soluble calcium salts and aqueous solutions of water-soluble phosphate and / or fluoride salts, the precipitation being carried out in the presence of protein components.
  • the protein components are added in pure, dissolved or colloidal form to the alkaline aqueous phosphate and / or fluoride salt solution or the alkaline solution of the calcium salt before the precipitation reaction.
  • the protein components can be presented in pure, dissolved or colloidal form and then the alkaline calcium salt solution and the alkaline phosphate and / or fluoride salt solution are added in succession in any order or simultaneously.
  • the individual components can in principle be put together in all possible orders.
  • Ammonia is preferably used as the alkalizing agent.
  • Another variant of the production process according to the invention is that precipitation from an acidic solution of a water-soluble calcium salt together with a stoichiometric amount of a water-soluble phosphate and / or fluoride salt or from an acidic solution of hydroxyapatite with a pH below 5 is preferred at a pH below 3, by raising the pH with aqueous alkali or ammonia in the presence of the protein components.
  • nanoparticulate calcium salts in pure or dispersed form or by precipitation reactions from aqueous solutions of water-soluble calcium salts and aqueous solutions of water-soluble phosphate and / or fluoride salts are mixed with the protein components, the latter preferably in dissolved or dispersed form , whereby any order can be chosen when adding.
  • the solution or dispersion of the protein component is preferably initially introduced and a dispersion of the nanoparticulate calcium salt is added.
  • the resulting dispersion of the composite material can, if required, be known by processes known to those skilled in the art, such as, B. Filtration or centrifugation separated from the solvent and the other constituents of the reaction mixture and by subsequent drying, for. B. by freeze-drying, be isolated in solvent-free form.
  • Water is preferably used as the solvent in all manufacturing processes; however, organic solvents such as e.g. B. alcohols with 1 to 4 carbon atoms or glycerol can be used.
  • the composite materials according to the invention in which the primary particles of the calcium salts are surface-modified, can be prepared by analogous precipitation processes as described above, but the precipitation of the nanoparticulate calcium salts or of the composite materials takes place in the presence of one or more surface modification agents.
  • the surface-modified nanoparticulate calcium salts are preferably first produced by a precipitation reaction between aqueous solutions of calcium salts and aqueous solutions of phosphate and / or fluoride salts in the presence of the surface modification agents. These can then be cleaned of accompanying products of the reaction mixture, e.g. B. by concentration under reduced pressure and subsequent dialysis. By stripping off the solvent, a dispersion of the surface-modified calcium salt with a solids content can additionally be produced as desired. Subsequently, by adding the protein components in pure, dissolved or colloidal form, the order of addition again being uncritical and, if necessary, after-reaction at elevated temperature, preferably in the range between 50 and 100 ° C. and for a duration of 1 to 100 minutes, that Composite material made of surface-coated calcium salt and protein components.
  • compositions for cleaning and / or caring for the teeth are suitable as remineralizing components for the production of compositions for cleaning and / or caring for the teeth.
  • the structured shape of the composites and the particle size of the calcium compounds contained therein enable the tooth enamel to be strengthened and lesions and dentinal tubules to be closed particularly quickly and completely.
  • the compositions for cleaning and maintaining the teeth can be present, for example, in the form of pastes, liquid creams, gels or mouthwashes. Even in liquid preparations, the composite materials according to the invention are easily distributed, remain stably dispersed and do not tend to sedimentation.
  • a preferred embodiment is toothpastes containing silica, polishing agents, humectants, binders and flavors, which contain 0.1-10% by weight of composite materials according to the invention with nanoparticulate calcium salts from the group of hydroxylapatite, fluorapatite and calcium fluoride.
  • the preparations for cleaning and caring for the teeth can contain the usual components and auxiliaries of such compositions in the usual amounts.
  • these are e.g. B.
  • Humectants such as B. glycerol, 1, 2-propylene glycol, sorbitol, xylitol and polyethylene glycols
  • Binder and consistency regulator e.g. B. natural and synthetic water-soluble polymers and water-soluble derivatives of natural products, for. B. Cellulose ethers, layered silicates, finely divided silicas (airgel silicas, pyrogenic silicas)
  • Flavors e.g. B. peppermint oil, spearmint oil, eucalyptus oil, anise oil, fennel oil, caraway oil, menthyl acetate, cinnamaldehyde, anethole, vanillin, thymol and mixtures of these and other natural and synthetic flavors
  • Sweeteners such as As saccharin sodium, sodium cyclamate, aspartame, acesulfan K, stevioside, moneliin, glycyrrhicin, dulcin, lactose, maltose or fructose
  • Preservatives and antimicrobial substances such as B. p-hydroxybenzoic acid ester, sodium sorbate, triclosan, hexachlorophene, phenylsalicylic acid ester, thymol etc.
  • Pigments such as B. titanium dioxide or pigment dyes to produce colored stripes
  • B. primary, secondary or tertiary alkali phosphates, citric acid / Na citrate wound healing and anti-inflammatory agents e.g. B. allantoin, urea, azulene, panthenol, acetylsalicylic acid derivatives, plant extracts, vitamins, e.g. B. retinol or tocopherol.
  • the composite materials according to the invention in particular those of hydroxyapatite and fluoroapatite, can induce or promote biomineralization in bone tissue. They are therefore still suitable as a biomineralizing component for the preparation of compositions for the restoration or regeneration of bone material, such as. B. of compositions for the treatment of bone defects and bone structures and to promote the ingrowth of implants.
  • the composite materials according to the invention can be applied, for example, according to the standard methods of dip coating or plasma spraying known to the person skilled in the art.
  • the composite materials according to the invention can be combined with suitable other substances, such as. B. glycosaminoglycans or proteins, and with suitable solvents and auxiliaries such. B. a dilute aqueous phosphate buffer.
  • type B gelatin (gelatin obtained by alkaline hydrolysis of bovine skin) were mixed with 100 ml of water and boiled once using a microwave.
  • the pH was 10.4 at the start of the dropping time and was kept at a pH of about 10 by replenishing ammonia solution. After a reaction time of 20 hours (25 ° C., with stirring), the pH of the aqueous suspension had dropped to 9.5.
  • the precipitated composite material was centrifuged off at 5000 rpm, washed with demineralized water at about 30-40 ° C. and freeze-dried. 2.2 g of composite material were obtained, the elemental analysis of which showed a carbon content of 2.3%; this corresponds to a protein material content of
  • composite materials were obtained from hydroxyapatite and the protein components described under 1.2 to 1.8.
  • solutions A and B were prepared separately.
  • This dispersion was added at room temperature to 100 ml of a 10% by weight aqueous solution of gelatin Bloom 300 (manufacturer: Fluka) prepared as in Example 1.1, then heated to 80 ° C. and stirred at this temperature for 5 minutes. The mass was then allowed to solidify at room temperature to form the composite material.
  • gelatin Bloom 300 manufactured as in Example 1.1
  • Plantacare ⁇ OO Ci2-C 16 alkyl glycoside approx. 50% by weight in water
  • Polywachs ® 1550 polyethylene glycol, MG: 1550 softening point 45 - 50 ° C manufacturer: RWE / DEA
  • Texapon ® K 1296 sodium lauryl sulfate powder Manufacturer: HENKEL KGaA
  • Cekol ® 500 T sodium carboxymethyl cellulose viscosity (2% in water, Brookfield LVF 20 ° C): 350 - 700 mPa s supplier: Nordmann-Rassmann
  • Tagat ® S polyoxyethylene (20) glyceryl monostearate Manufacturer: Tego Cosmetics (Goldschmidt)

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Abstract

La présente invention concerne des matériaux composites comprenant des sels de calcium difficilement solubles dans l'eau tels les sulfates et fluorosulfates de calcium, lesdits sels de calcium se présentant sous forme de nanoparticules de diamètre moyen compris entre 10 et 300 nm. Ces matériaux composites comprennent également des composantes protéiques choisies parmi les protéines, les hydrolysats protéiques et les dérivés d'hydrolysats protéiques. Ces matériaux composites conviennent comme éléments reminéralisants dans des compositions de nettoyage et de soins dentaires ainsi que pour stimuler la régénération des tissus osseux.
EP00951293A 1999-07-02 2000-06-23 Materiaux composites constitues de composes de calcium et de composantes proteiques Expired - Lifetime EP1189582B1 (fr)

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DE20023797U DE20023797U1 (de) 1999-07-02 2000-06-23 Kompositmaterialien aus Calciumverbindungen und Proteinkomponenten
EP06004167A EP1676555A3 (fr) 1999-07-02 2000-06-23 Matériaux composites constitués de composés de calcium et de composantes protéiques

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DE19930335A DE19930335A1 (de) 1999-07-02 1999-07-02 Kompositmaterialien aus Calciumverbindungen und Proteinkomponenten
PCT/EP2000/005813 WO2001001930A2 (fr) 1999-07-02 2000-06-23 Materiaux composites constitues de composes de calcium et de composantes proteiques

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Publication number Publication date
WO2001001930A3 (fr) 2001-07-12
EP1676555A2 (fr) 2006-07-05
ES2260037T3 (es) 2006-11-01
ATE319406T1 (de) 2006-03-15
AT8957U1 (de) 2007-03-15
DE20023797U1 (de) 2006-05-24
CA2373955C (fr) 2011-04-26
DK1189582T3 (da) 2006-07-17
AU6428500A (en) 2001-01-22
WO2001001930A2 (fr) 2001-01-11
CA2373955A1 (fr) 2001-01-11
JP2003503434A (ja) 2003-01-28
DE19930335A1 (de) 2001-01-18
EP1189582B1 (fr) 2006-03-08
JP4707909B2 (ja) 2011-06-22
US20080160091A1 (en) 2008-07-03
DE50012369D1 (de) 2006-05-04
EP1676555A3 (fr) 2009-06-17

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